Alpha-1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine (NE). Currently, several subtypes of the alpha-1 adrenergic receptors are known to exist for which the genes have been cloned: alpha-1A (previously known as alpha-1C), alpha-1B and alpha-1D. Recently the existence of a low affinity alpha-1 adrenoceptor for prazosin named alpha-1L, in human prostate has been determined. However, the gene for the alpha1L-adrenergic receptor subtype has yet to be cloned.
Alpha-1 adrenoceptor antagonists have been shown in numerous clinical studies to be effective in relieving the symptoms associated with benign prostatic hypertrophy, also known as benign prostatic hyperplasia (BPH), an illness typically affecting men over fifty. The symptoms of the condition include, but are not limited to increased difficulty in urination and sexual dysfunction. Drugs such as prazosin, indoramin, doxazosin and tamsulosin are in common clinical use for BPH, and are effective in reducing both “obstructive” symptoms (eg. weak stream) and “irritative” symptoms (eg. urinary urge and frequency, nocturia). However, these compounds are all non-subtype-selective, and have the potential to cause significant side-effects, particularly cardiovascular effects such as postural hypotension, dizziness and syncope, and CNS effects including aesthenia (tiredness). These effects can limit dosing and thus clinical efficacy in reducing symptoms associated with BPH.
Pharmacological studies resulting in the subdivision of alpha-1 adrenoceptors into alpha-1A, alpha-1B and alpha-1D adrenoceptors have led to the suggestion that development of subtype-selective antagonists may allow improved symptomatic treatment of BPH/unstable bladder with a lower incidence of dose-limiting side-effects. Recently, much interest has been focused on the role of the alpha-1A adrenoceptor subtype in BPH, as a result of studies demonstrating that this subtype predominates in the urethra and prostate of man (Price et al., J. Urol., 1993, 150, 546-551; Faure et al., Life Sci., 1994, 54, 1595-1605; Taniguchi et al., Naunyn Schmiedeberg's Arch. Pharmacol., 1997, 355, 412-416), and appears to be the receptor mediating NE-induced smooth muscle contraction in these tissues (Forray et al., Mol. Pharmacol., 1994, 45, 703-708; Hatano et al., Br. J. Pharmacol., 1994; 113, 723-728; Marshall et al., Br J. Pharmacol., 1995, 115, 781-786). The resulting smooth muscle tone is believed to contribute substantially to the total urinary outflow obstruction observed in patients with BPH (Furuya et al., J. Urol., 1982, 128, 836-839), with the remaining being attributable to increased prostate mass. These observations have fuelled the hypothesis that an alpha-1A subtype-selective antagonist may, via a selective and significant decrease in outlet resistance, lead to improved pharmacotherapy for BPH.
However, it must be noted that in BPH, it is often the irritative symptoms which prompt the patient to seek treatment, and that these irritative symptoms may be present even in patients with no demonstrable obstruction (i.e. normal urine flow rates). Recently in U.S. patent application Ser. No. 09/521,185 Ford et al. have described the use of selective alpha-1B adrenoceptor antagonists for the treatment of disorders resulting in irritative bladder symptoms. The current proposal is that by combining both alpha-1A and alpha-1B subtype selectivity in a drug molecule, it would be possible to reduce both obstructive and irritative symptoms in patients with BPH. The lack of alpha-1D adrenoceptor antagonism is expected to lead to reduced or fewer side effects than those associated with the use of non-subtype-selective agents.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.